The communication between metabolic tissues and immune cells maintains tissue homeostasis. Skeletal muscle is a unique tissue for studying the intersection of metabolic and immune signals because of its high metabolic demand and need for non-pathological inflammatory repair. After exercise, neutrophils and macrophages are recruited to muscle to remove damaged tissue and facilitate muscle regeneration and resolution of inflammatory response. As such, repeated endurance exercise has anti-inflammatory effects. Several studies have indicated that the increased oxidative capacity, mitochondrial mass, and reduced metabolic inflammation as a result of endurance exercise protect against the development of metabolic disease. However, how exercise alters immune and metabolic programs to promote metabolic benefits remains unclear. Preliminary studies suggest a role for the Th2 cytokine interleukin-13 (IL-13) in skeletal muscle oxidative metabolism. Notably, IL-13-/- mice exhibit reduced oxidative type I muscle fibers and running capacity. The action of IL-13 on skeletal muscle appears to be mediated by a no canonical downstream transcription factor, the activation of signal transducer and activator of transcription 3 (STAT3). In the current research plan, we propose to test the hypothesis that the IL-13/STAT3 axis in muscle plays a key role in mitochondrial oxidative phosphorylation, type I muscle development and metabolic homeostasis in endurance exercise. This hypothesis will be examined in two aims using molecular/cellular approaches and mouse genetic models. Knowledge derived from this study is expected to fill in a major gap in our understanding of how exercise training enhances metabolic homeostasis.